Nature Communications (Jul 2023)
Defining the landscape of circular RNAs in neuroblastoma unveils a global suppressive function of MYCN
- Steffen Fuchs,
- Clara Danßmann,
- Filippos Klironomos,
- Annika Winkler,
- Jörg Fallmann,
- Louisa-Marie Kruetzfeldt,
- Annabell Szymansky,
- Julian Naderi,
- Stephan H. Bernhart,
- Laura Grunewald,
- Konstantin Helmsauer,
- Elias Rodriguez-Fos,
- Marieluise Kirchner,
- Philipp Mertins,
- Kathy Astrahantseff,
- Christin Suenkel,
- Joern Toedling,
- Fabienne Meggetto,
- Marc Remke,
- Peter F. Stadler,
- Patrick Hundsdoerfer,
- Hedwig E. Deubzer,
- Annette Künkele,
- Peter Lang,
- Jörg Fuchs,
- Anton G. Henssen,
- Angelika Eggert,
- Nikolaus Rajewsky,
- Falk Hertwig,
- Johannes H. Schulte
Affiliations
- Steffen Fuchs
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Clara Danßmann
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Filippos Klironomos
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Annika Winkler
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Jörg Fallmann
- Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, University of Leipzig
- Louisa-Marie Kruetzfeldt
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Annabell Szymansky
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Julian Naderi
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Stephan H. Bernhart
- Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, University of Leipzig
- Laura Grunewald
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Konstantin Helmsauer
- Experimental and Clinical Research Center (ECRC) of the Charité and Max-Delbrück-Center for Molecular Medicine (MDC) in the Helmholtz Association
- Elias Rodriguez-Fos
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Marieluise Kirchner
- Core Unit Proteomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC)
- Philipp Mertins
- Core Unit Proteomics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine (MDC)
- Kathy Astrahantseff
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Christin Suenkel
- Systems Biology of Gene Regulatory Elements, Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association
- Joern Toedling
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Fabienne Meggetto
- CRCT, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse
- Marc Remke
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Heinrich Heine University Düsseldorf, Medical Faculty, and University Hospital Düsseldorf
- Peter F. Stadler
- Bioinformatics Group, Department of Computer Science, and Interdisciplinary Center for Bioinformatics, University of Leipzig
- Patrick Hundsdoerfer
- Department of Pediatric Oncology, Helios Klinikum Berlin-Buch
- Hedwig E. Deubzer
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Annette Künkele
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Peter Lang
- Department I - General Pediatrics, Hematology/Oncology, University Children’s Hospital, Eberhard Karls University Tuebingen
- Jörg Fuchs
- Department of Pediatric Surgery and Pediatric Urology, University Children’s Hospital, Eberhard Karls University Tuebingen
- Anton G. Henssen
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Angelika Eggert
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Nikolaus Rajewsky
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Falk Hertwig
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- Johannes H. Schulte
- Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin
- DOI
- https://doi.org/10.1038/s41467-023-38747-4
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 21
Abstract
Abstract Circular RNAs (circRNAs) are a regulatory RNA class. While cancer-driving functions have been identified for single circRNAs, how they modulate gene expression in cancer is not well understood. We investigate circRNA expression in the pediatric malignancy, neuroblastoma, through deep whole-transcriptome sequencing in 104 primary neuroblastomas covering all risk groups. We demonstrate that MYCN amplification, which defines a subset of high-risk cases, causes globally suppressed circRNA biogenesis directly dependent on the DHX9 RNA helicase. We detect similar mechanisms in shaping circRNA expression in the pediatric cancer medulloblastoma implying a general MYCN effect. Comparisons to other cancers identify 25 circRNAs that are specifically upregulated in neuroblastoma, including circARID1A. Transcribed from the ARID1A tumor suppressor gene, circARID1A promotes cell growth and survival, mediated by direct interaction with the KHSRP RNA-binding protein. Our study highlights the importance of MYCN regulating circRNAs in cancer and identifies molecular mechanisms, which explain their contribution to neuroblastoma pathogenesis.
